An early disclosure of sustained release pharmaceutical preparations appears in U.S. Pat. No. 2,990,332 to Keating wherein a sulphonic acid cation exchange resin is employed. A pharmaceutical is ionically bonded or adsorbed onto an ion exchange resin particle. One requirement of the pharmaceutical is that it contains a basic functional group.
Thereafter, ion exchange resin drug complexes were provided with a diffusion barrier coating that provided delayed action by the gastric juices of the person being treated with the drug. An early example of such preparations is U.S. Pat. No. 4,221,778 to Raghunathan wherein the resins provided were various polymeric matrices including AMBERLITE IR120, a cationic exchange resin as well as AMBERLITE XE69, which is a smaller sized resin particle derived from AMBERLITE IR120. Other ion exchange resins mentioned were methacrylic, acrylic, phenol formaldehyde ion exchange agents with cellulosic or dextran polymer matrices and inorganic ion exchange matrices. In the '778 patent, ethylcellulose was employed as a water-permeable, diffusion barrier coating over the ion exchange resin particle.
There followed numerous publications wherein the ion exchange resins were treated with hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sorbitol, hydroxypropyl sorbitol and polyvinlylpyrrolidone. One example of this is U.S. Pat. No. 4,859,461 to Chow et al. Varying the thickness of the polymeric coatings provides the duration of extended release. A variation of the organic coating of the resin particle is disclosed in U.S. Pat. No. 4,894,239 to Nonomura et al. In this patent a water permeable layer is applied to the resin particle. In one example dihydrocodeine phosphate was converted to the free base in ethanol and combined with a cation exchange resin. The loaded resin was then separated, dried and then coated with aminoalkyl methacrylate in acetone. An eight-hour release pattern was produced by this particle.
Another approach to sustained release medication is found in U.S. Pat. No. 5,968,551 to Oshlack and Chassin, wherein a unit dose of opioid is provided by constructing an array of different sized particles ranging in size from 0.1 mm to 3 mm. In some embodiments spherical particles are provided but then coated with materials such as ethylcellulose or water-soluble cellulose such as hydroxy lower alkyl cellulose. Various solvent coating processes are disclosed. In addition, a melt pelletization method is disclosed wherein the opioid is combined with a binder and other optional ingredients. The binder material containing the opioid is then pelletized with a high shear mixer to obtain the required sizes.
Another process is described in U.S. Published Application 2002/0031490. The process is based upon a resin that can be hydrated with a small amount of water whereby the resin absorbs the active material that is relatively insoluble in the amount of water employed. In this system the active is at least partially dissolved in a solvent. Thus, a solvent system is also disclosed wherein the hydrated resin is dispersed in a solvent for the active. Solvents include organic solvents such as ethanol, dichloroethane and 1,1,1,2-tetrafluoroethane.
Other examples of various sustained release formulations involving coated resin particles include U.S. Pat. Nos. 6,001,392; 6,228,398; 4,996,047; 4,959,219; 4,847,077; 4,762,709; 4,690,933 and EP 911 039.
The prior art has disclosed sustained release compositions and processes that include a coating or coating step. It would be advantageous to provide a sustained release pharmaceutical particle by a process that does not require a polymer film coating for controlled drug delivery because such processes are lengthy and expensive.